HMGCS2对APP代谢的影响及其机制研究

发布时间：2018-09-08 16:22

【摘要】：线粒体3-羟基-3甲基戊二酰辅酶A合成酶2(mitochondrial3-hydroxy-3-methylglutaryl-CoA synthase 2,mHMGCS2)是酮体生成的限速酶,其线粒体定位和与β-淀粉样前体蛋白(β-amyloid precursor protein,APP)间的相互作用均提示HMGCS2可能在AD的发病机制中起一定的作用。在我们的研究中,HMGCS2过表达显著地降低了APP及其相关的羟基末端片段(carboxy-terminal fragments,CTFs)的水平,而自噬抑制剂氯喹(chloroquine,CQ)却有效地阻断了HMGCS2过表达减低APP的效应。值得注意的是,mTOR(mechanist target of rapamycin)抑制剂雷帕霉素(rapamycin,Rapa)却减弱了HMGCS2增强的自噬标志物LC3-Ⅱ蛋白信号,并且Earle’s平衡盐溶液(Earle’s Balaced salt solution,EBSS)显著地增强了HMGCS2过表达促LC3-Ⅱ蛋白效应,而反之,乙酰乙酸(acetoacetate,AcAc)则有效地逆转了因HMGCS2敲低而减低LC3-Ⅱ蛋白和而增高的APP及其CTFs的效应。同时,类似于HMGCS2过表达细胞,促自噬Rapa在AcAc处理的细胞中并没有进一步增强LC3-Ⅱ蛋白的表达。此外,HMGCS2增强了HT22细胞抗氧化能力。最后,HMGCS2在7月龄APP/PS1小鼠的海马组织中表达下调。综上所述,HMGCS2与酮体在促进APP及其CTFs自噬性降解方面具有共同的特征,提示酮体在HMGCS2的自噬调节中起重要作用。
[Abstract]:Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (mHMGCS2) is a rate-limiting enzyme produced by ketone. Its mitochondrial localization and interaction with beta-amyloid precursor protein (APP) suggest that HMGCS2 may play a role in the pathogenesis of AD. In our study, HMGCS2 overexpression significantly reduced the levels of APP and its related carboxy-terminal fragments (CTFs), while chloroquine (CQ), an autophagy inhibitor, effectively blocked the effect of HMGCS2 overexpression on APP reduction. Rapamycin (Rapa) weakened the signal of LC3-II protein, an autophagy marker enhanced by HMGCS2, and Earle's Balaced Salt Solution (EBSS) significantly enhanced the effect of over-expression of HMGCS2 on LC3-II protein, whereas acetoacetate (Ac) effectively reversed the decrease due to the knockdown of HMGCS2. In addition, HMGCS2 enhanced the antioxidant capacity of HT22 cells. Finally, the expression of HMGCS2 was down-regulated in the hippocampus of 7-month-old APP/PS1 mice. HMGCS2 and ketone have the same characteristics in promoting autophagic degradation of APP and CTFs, suggesting that ketone plays an important role in autophagic regulation of HMGCS2.
【学位授予单位】：重庆医科大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R749.16

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